title: In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles.
abstract: Gemcitabine (Gemzar(®)) is the first line treatment for pancreatic cancer and often used in combination therapy for non-small cell lung, ovarian, and metastatic breast cancers. Although extremely toxic to a variety of tumor cells in culture, the clinical outcome of gemcitabine treatment still needs improvement. In the present study, a new gemcitabine nanoparticle formulation was developed by incorporating a previously reported stearic acid amide derivative of gemcitabine into nanoparticles prepared from lecithin/glyceryl monostearate-in-water emulsions. The stearoyl gemcitabine nanoparticles were cytotoxic to tumor cells in culture, although it took a longer time for the gemcitabine in the nanoparticles to kill tumor cells than for free gemcitabine. In mice with pre-established model mouse or human tumors, the stearoyl gemcitabine nanoparticles were significantly more effective than free gemcitabine in controlling the tumor growth. PEGylation of the gemcitabine nanoparticles with polyethylene glycol (2000) prolonged the circulation of the nanoparticles in blood and increased the accumulation of the nanoparticles in tumor tissues (>6-fold), but the PEGylated and un-PEGylated gemcitabine nanoparticles showed similar anti-tumor activity in mice. Nevertheless, the nanoparticle formulation was critical for the stearoyl gemcitabine to show a strong anti-tumor activity. It is concluded that for the gemcitabine derivate-containing nanoparticles, cytotoxicity data in culture may not be used to predict their in vivo anti-tumor activity, and this novel gemcitabine nanoparticle formulation has the potential to improve the clinical outcome of gemcitabine treatment.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Sloat
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandoval
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Woon-Gye
authors.initials: WG
authors.lastname: Chung
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Proteau
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kiguchi
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005079:Excipients / Q000737:chemistry; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D013229:Stearic Acids / Q000737:chemistry*; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D005079:Excipients; D013229:Stearic Acids; D003841:Deoxycytidine; D011092:Polyethylene Glycols; C031183:stearic acid; D000093542:Gemcitabine